Tubulointerstitial nephritis may occur spontaneously, but it is most often observed in the context of other pathologic processes in the course of renal failure, and it is highly predictive of end stage disease. Although these lesions are characterized by infiltrations of mononuclear cells, the cellular and molecular events leading to the invasion are not fully understood. Mice with the kd/kd genotype have a spontaneously occurring kidney disease, which is characterized by normal appearing kidneys at birth, leukocyte infiltrations at eight weeks, and progression to end stage disease thereafter. These mice have a defect in a gene for a prenyltransferase-like mitochondrial protein (PLMP), and they have ultrastructural defects in the mitochondria of the kidney and other tissues. These defects lead to potent stimulation of autoimmunity and inflammation, and this can occur without a functional Rag-1 gene. Based on these findings, we postulate that the genetic defect expressed in the mitochondria of the kidney renders epithelial cells more susceptible to cell injury and death. This in turn leads to inflammation, fibrosis and progressive renal failure. We further postulate that this sequence of events, although magnified in kd/kd homozygotes, may represent a general paradigm for progressive renal failure, whereby genetically determined responses to injury may influence disease progression. These hypotheses will be addressed through the following specific Aims: (1) to investigate the contributions of different cells and tissues to the pathogenesis of this disease, (2) to investigate the roles of NK and NKT cells, and to explore the circumstances under which kd/+ mice develop interstitial nephritis, and (3) to investigate the specific mitochondrial defect in kd/kd mice. The results of these studies have the potential to provide general insights into the events leading to progressive renal failure, independently of the processes that initiate disease. Developing a better understanding of these events has the potential to lead to novel therapies for human patients with progressive renal disease. [unreadable] [unreadable] [unreadable]